Bisphosphonates represent a class of drugs that have shown very promising therapeutic efficacy in the treatment of a number of diseases associated with abnormally accelerated bone resorption including; osteoporosis, Paget's disease and hypercalcemia of malignancy. Fleisch H., Ann Med, 29, 55-62 (1997) and Fleisch H., Drugs, 42, 919-944 (1991). More recently bisphosphonates have been shown to be effective at lowering the risk of developing skeletal complications (e.g., pathologic fractures, spinal-cord compression, the need for bone surgery or irradiation) in patients with prostate cancer that had spread to the bone, Saad F et al., J National Cancer Institute 94:1458-1468, 2002; and to inhibit the proliferation of RAS-dependent malignancies, e.g., small cell lung cancer Matsumoto, et al., Am. Soc. of Clin. Oncology, 2003, Abst. No. 2750. Bisphosphonates have also been shown to have antiangiogenic activty, Wood et al, J Pharmacol Exp Ther 2002 September; 302(3):1055-61. Bisphosphonates are commonly used for treatment of myeloma bone disease and against osteolytic metastases of breast cancer, and clinical studies have suggested their use to relieve pain in metastatic prostate cancer.
Platinum-based agents are widely utilized in chemotherapeutic applications. For example, cisplatin kills tumor cells via formation of covalent, cross- or intrastrand DNA adducts (Sherman et al. Chem. Rev., 87, 1153-81 (1987); Chu, J. Biol. Chem., 269, 787-90 (1994)). Treatment with such platinum-based agents thereby leads to the inhibition of DNA synthesis (Howle et al., Biochem. Pharmacol., 19, 2757-62 (1970); Salles et al., Biochem. Biophys. Res. Commun., 112, 555-63 (1983)). Thus, cells actively synthesizing DNA are highly sensitive to cisplatin (Roberts et al., Prog. Nucl. Acid Res. Mol. Biol., 22, 71-133 (1979); Pinto et al., Proc. Nat. Acad. Sci. (Wash.) 82, 4616-19 (1985)). Such cells generally experience a growth arrest in G2 and eventually undergo apoptosis. This apoptotic effect is observed at drug concentrations insufficient to inhibit DNA synthesis (Sorenson et al, J. Natl. Cancer Inst., 82, 749-55 (1990)), suggesting that platinum agents act on neoplastic cells via multiple mechanisms. Some cells also demonstrate increased platinum sensitivity when in the G1 phase of the cell cycle (Krishnaswamy et al., Mutation Res., 293, 161-72 (1993); Donaldson et al., Int. J. Cancer, 57, 847-55 (1994)). Upon release from G0/G1-S block, such cells remain maximally sensitized through the remainder of the cell cycle.
U.S. Pat. No. 6,087,349 discloses that bisphosphonates can act as protein-prenyl transferase inhibitors.
U.S. Pat. No. 4,746,654 discloses bisphosphonates useful as anti-inflammatory agents.
Australian Patent A-5 1534/85 discloses bisphosphonates useful in treating abnormal calcium and phosphorous metabolism and useful in treating arthritis.
U.S. Pat. No. 3,683,080 discloses polyphosphonates, in particular diphosphonates useful in inhibiting anomalous deposition and mobilization of calcium phosphate in animal tissue.
DE 3,719,513-A (Derwent 89-000580/01) discloses diphosphonic acid derivatives useful in treatment of disorders of calcium metabolism.
WO88/06158 discloses the reaction of activated methylenes with vinylidene diphosphonates.
International Publication Number WO90/12017 for International Application Number PCT/US90/01106 discloses geminal bisphosphonic acids and derivatives thereof as anti-arthritic agents.
United States Patent Application No. 20020022603 discloses compositions of zwitterionic phospholipids and bisphosphonates and use of such compositions as bisphosphate delivery systems with reduced GI toxicity.
United States Patent Application No. 20030032628 discloses pharmaceutical compositions of bisphosphonic acids, and salts thereof, prepared by wet granulation tablet formulation. These pharmaceutical compositions are said to be prepared without the addition of binder; instead, the drug itself acts as a binder.
United States Patent Application 20020002140 discloses glycosides and orthoester glyco side derivatives of bisphosphonate compounds which are said to have markedly enhanced intestinal absorption and enhanced bioavailability.
U.S. Pat. No. 5,133,972 discloses transdermal delivery phosphate compounds, and in particular bisphosphonates. Relatedly, U.S. Pat. No. 6,018,679 discloses a method for iontophoretically removing compounds capable of causing skin irritation or other harmful effects.
U.S. Pat. No. 6,114,316 discloses compositions which combine a tetracycline and a bisphosphonate in synergistic proteinase inhibiting amounts to treat or prevent tissue-destructive conditions related to excess proteinase activity in a biological system.
U.S. Pat. No. 6,214,812 discloses bisphosphonate conjugates which are said to be capable of releasing antibacterial and/or cytotoxic components upon binding with bone tissue.
U.S. Pat. No. 6,436,386 discloses hydroxyapatite-targeting polymeric structures, and biologically active conjugates thereof, wherein the hydroxyapatite-targeting moiety may be a bisphosphonate. The conjugates are said to provide a means for tethering a biologically active substances to bone surface.
Numerous other references may be found in the art describing various types of bisphosphonate compounds, conjugates, formulations, combinations and uses thereof. However there is not disclosed therein a method of synthesizing bisphosphonate complexes comprising platinum, palladium, or like moieties, that are therapeutically useful. Other bisphosphonate complexes known in the art were not known to possess superior properties in respect of their use as therapeutic agents, particularly in respect of their use for the treatment of cancer, more particularly with respect to their use for the treatment of cancers affecting bone tissue.